纤毛发生在进行性听力损失中的作用研究

Progressive hearing loss is a common disease in Hong Kong, with 10% of all ages and 60% of those over 65 years old have debilitating hearing loss with degenerating hair cells. Although genes involved in Progressive hearing loss have been reported, little is known about the molecular mechanisms. ..Haploinsufficiency for EYA1 causes branchio-oto-renal syndrome which have been associated with Progressive hearing loss. Inactivation of Eya1 in mice results in early arrest of inner ear development at the otic vesicle stage. However, the roles of Eya1 in hair cell development at later stages are still unknown. ..In this project, we conditionally knockout Eya1 in hair cells at E15.5 when the cilium starts to migrate. Migration of the kinocilium and hair bundle orientation and shape in cochlear hair cells were affected in Eya1cko mutants similar to the reported Rac1cko and Cdc42cko mutants in G-protein signalling pathway. Based on our initial observations, we hypothesize that Eya1 is required in cilium migration, planar cell polarity and actin polymerization for hair bundle formation...In this project, we propose to i) examine the expression pattern of Eya1 on hair cell cilia bundle; ii) characterize the role of Eya1 on hair cell cilia bundle formation using mutant mouse models; iii) delineate the mechanism of Eya1 and G-protein signalling in cell polarity and cilium migration in hair cells by cellular and molecular analyses...This study will provide new understanding of Eya1 function in mammalian cochlear hair bundle development and lead to the discovery of novel functions of Eya1 as underlying mechanisms of human progressive hearing loss and new treatments for human deafness. .

进行性听力损失是一种相当普遍的疾病,听觉能力随着年龄的增长而逐渐下降,大约其中有60% 为65岁以上的老年人患有由听觉细胞退化所造成的听力减退。尽管已经有进行性听力损失相关的基因报道，但是其具体的分子机制仍旧未知。Eya1基因突变在腮耳肾Branchio-Oto-Renal syndrome综合症中与人类听力损失有关。在Eya1 突变小鼠中发现严重的早期的内耳发育缺陷。然而，Eya1在后期毛细胞发育中的作用仍然未知。在本研究中，我们拟运用突变小鼠模型研究Eya1在毛细胞纤毛束形成中的作用；通过细胞和分子的方法，研究Eya1和G-蛋白信号在毛细胞的细胞极性和纤毛迁移中的作用机理。这项研究将使人们对Eya1在毛细胞纤毛束发育中的作用产生崭新认识，并将发现Eya1在纤毛形成中的新功能，这可能是人类进行性听力损失的潜在机制以及人类耳聋的新型疗法。

进行性听力损失是一种相当普遍的疾病,听觉能力随着年龄的增长而逐渐下降,大约其中有.60% 为65岁以上的老年人患有由听觉细胞退化所造成的听力减退。尽管已经有进行性听力.损失相关的基因报道，但是其具体的分子机制仍旧未知。Eya1基因突变在腮耳肾Branchio.-Oto-Renal syndrome综合症中与人类听力损失有关。在Eya1 突变小鼠中发现严重的早期.的内耳发育缺陷。然而，Eya1在后期毛细胞发育中的作用仍然未知。在本研究中，我们拟.运用突变小鼠模型研究Eya1在毛细胞纤毛束形成中的作用；通过细胞和分子的方法，研究.Eya1和G-蛋白信号在毛细胞的细胞极性和纤毛迁移中的作用机理。这项研究使人们对Ey.a1在毛细胞纤毛束发育中的作用产生崭新认识，并发现Eya1在纤毛形成中的新功能，这.可能是人类进行性听力损失的潜在机制以及人类耳聋的新型疗法。